Smad signaling in the rat model of monocrotaline pulmonary hypertension

Toxicol Pathol. 2008 Feb;36(2):311-20. doi: 10.1177/0192623307311402. Epub 2008 Mar 26.

Abstract

Mutations in the bone morphogenetic protein receptor type II (BMPrII) gene have been implicated in the development of familial pulmonary artery hypertension (PAH). The function of BMP signal transduction within the pulmonary vasculature and the role BMPrII mutations have in the development of PAH are incompletely understood. We used the monocrotaline (MCT) model of PAH to examine alterations in Smad signal transduction pathways in vivo. Lungs harvested from Sprague-Dawley rats treated with a single 60-mg/kg intraperitoneal (IP) injection of MCT were compared to saline-treated controls 2 weeks following treatment. Smad 4 was localized by immunohistochemistry to endothelial nuclei of the intra-acinar vessels undergoing remodeling. Smad 4, common to both BMP and transforming growth factor beta (TGFbeta) signaling, and BMP-specific Smad 1 were significantly decreased in western blot from whole lungs of treated animals, while no change was found for TGFbeta-specific Smad 2. MCT-treated rats also had increased expression of phosphorylated Smad 1 (P-Smad 1) but not phosphorylated Smad 2 (P-Smad 2). There was a decrease in the expression of the full BMPrII protein but not its short form variant in MCT-treated rat lungs. The type I receptor Alk1 had increased expression. Collectively, our data indicate that vascular remodeling in the MCT model is associated with alterations in BMP receptors and persistent endothelial Smad 1 signaling.

MeSH terms

  • Activin Receptors / metabolism*
  • Animals
  • Bone Morphogenetic Protein Receptors, Type II / metabolism*
  • Bone Morphogenetic Proteins / metabolism
  • Disease Models, Animal
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Hypertension, Pulmonary / chemically induced
  • Hypertension, Pulmonary / metabolism*
  • Injections, Intraperitoneal
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Monocrotaline / toxicity*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction
  • Smad1 Protein / metabolism
  • Smad2 Protein / metabolism
  • Smad4 Protein / metabolism*
  • Transforming Growth Factor beta / metabolism

Substances

  • Acvrl1 protein, rat
  • Bone Morphogenetic Proteins
  • Receptors, Transforming Growth Factor beta
  • Smad1 Protein
  • Smad1 protein, rat
  • Smad2 Protein
  • Smad2 protein, rat
  • Smad4 Protein
  • Smad4 protein, rat
  • Transforming Growth Factor beta
  • Monocrotaline
  • Activin Receptors
  • Bmpr2 protein, rat
  • Bone Morphogenetic Protein Receptors, Type II